Catheter-associated urinary tract infection (CAUTI) is the most common type of hospital-acquired infection accounting to about 30% of the infections reported by acute care hospitals in the United States and affecting millions of patients worldwide annually [1-4]. Like other nosocomial infections on medical implants, CAUTI involves the formation of pathogenic biofilms on the surface of urinary catheters. Pathogenic bacteria in the biofilms are embedded in a self-produced polymer matrix, which protect themselves against antimicrobial agents, and facilitate the development of resistance to antibiotics [1, 5-8]. To inhibit biofilm formation, one of the most studied strategies includes the incorporation of antimicrobial agents to urinary catheters, which are mostly made of silicone polymers [9-13]. While some of the results encouraged further development, many appeared not promising, especially those relevant to long-term catheter use [2, 3, 14]. A great challenge to overcome is to completely prevent biofouling on the catheters, which blocks the antimicrobial agents and provides a new platform for growing biofilms [2]. While recent studies on antifouling coatings against bacterial adhesion has made impressive progress [9, 15-17], the rapidly increasing pressure of antibiotic resistance and cost for treatment of CAUTI has called to speed up the development of alternative strategies [7, 18].
One alternative strategy is based on bacterial interference using benign biofilms of probiotic bacteria to protect against the attachment and colonization of pathogens [19-24]. An example of probiotic bacteria, also called “friendly bacteria” or “good bacteria”, is the beneficial bacteria found in the human gut [25]. Despite some of the potential safety concerns, such as gene transfer and pathogenicity, it has been proven that probiotics are vital to proper health maintenance [26, 27]. They have been used as dietary supplements and drug against various bowel disease [25, 26], and investigated for preventing CAUTI and bacterial vaginosis [28-33]. In clinical trials, probiotic E. coli 83972 have successfully colonized bladders leading to a significant decrease in the frequency of urinary tract infection without notable side effects [22-24, 34, 35]. As compared to antimicrobial coatings that are prone to leaching and fouling [21, 30, 32, 36], the living biofilms of probiotic bacteria grown on catheters actively produce molecules to outcompete a wide range of aggressive pathogens. This unique feature has rendered bacterial interference one of the most promising approaches for preventing CAUTI.
Despite of its great potentials, the effectiveness of the bacterial interference approach relies greatly on the establishment of a high coverage, stable pre-formed benign biofilms on the surface. Pre-inoculation of urinary catheters with E. coli 83972 was used to introduce the benign bacteria to the bladder. However, it has been shown that E. coli 83972 and several other benign bacteria adhered less and formed biofilms more slowly on silicone surfaces than common uropathogens [37]. Interestingly, the results were the opposite on solid substrates (glass and polystyrene tissue culture plates) [37]. Thus, the utility of the benign biofilms on silicone catheter to outcompete challenge pathogens had been limited to relatively short bacterial interference time (30 min) [38, 39], while prolonged exposure led to detachment and significant decrease in coverage of the benign E. coli on the silicone catheter surface [40].
Biofilm formation is enhanced by the presence of adhesins including type 1 fimbriae present on most E. coli strains [41]. However, the wild-type E. coli 83972 does not express the common type 1 fimbriae because of its incomplete fim operon [42]. A transformed E. coli 83972 strain expressing type 1 fimbriae (fim+E. coli 83972) improved the biofilm formation on urinary catheters [43]. Since type 1 fimbriae binds mannose ligands [44], many E. coli strains expressing type 1 fimbriae have a high affinity to mannose-presenting surfaces [45-49]. It has also been demonstrated that the adherence of uropathogens is significantly reduced if a biofilm of fim+E. coli is pre-coated on the substrates [38, 39], including the mannose-modified single crystal silicon substrates. Therefore, we anticipated that covalent modification of silicone catheters would increase the coverage and stability of the biofilms of fim+E. coli 83972 and improve the efficiency for bacterial interference.